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<p>Chronic inflammation drives the pathogenesis of diverse disorders, yet current anti-inflammatory strategies often lack mechanistic selectivity. Glycyrrhizic acid (GL), a major triterpenoid saponin from Glycyrrhiza species, exhibits broad anti-inflammatory effects, but its mechanism has been viewed as non-specific. In this review, we propose an integrated framework positioning high-mobility group box 1 (HMGB1) as one major molecular hub for GL’s action. Mechanistically, our molecular docking analysis suggests that GL may interact with the Box B domain of HMGB1 andmay potentially interfere with its engagement with TLR4 and RAGE, thereby orchestrating a cascade inhibition of downstream NF-κB, MAPK, and NLRP3 inflammasome pathways. Beyond this core signaling axis, we systematically analyze how GL context-dependently modulates macrophage polarization, monocyte-derived macrophage differentiation, and Th17/Treg balance. We further synthesize its effects across liver, autoimmune, metabolic, oncologic, neurological, and renal diseases, revealing shared mechanisms and disease-specific adaptations. Finally, we critically evaluate translational bottlenecks—including isomer-specific bioavailability, the pseudoaldosteronism risk, and formulation challenges—and propose strategies to overcome them. By shifting from a descriptive summary to a mechanism-centered, integrative analysis, this review provides a conceptual framework for developing GL as a multitarget anti-inflammatory agent, while acknowledging its limitations including low oral bioavailability, microbiota-dependent metabolism, pseudoaldosteronism risk, and limited clinical evidence.</p>

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Therapeutic potential of glycyrrhizic acid in inflammation-related diseases: from HMGB1-oriented molecular insights to preclinical application

  • 期刊论文

  • 发表日期：

    2026年6月17日

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  • Yicheng Hu,
  • Jiani Hou,
  • Yifeng Cai,
  • Chaoran Ni,
  • Zhewen Xing,
  • Jingtian Li,
  • Zan Zhou,
  • Guangtao Xu,
  • Xiansi Zeng,
  • Jinjing Jia,
  • Li Li

摘要

Chronic inflammation drives the pathogenesis of diverse disorders, yet current anti-inflammatory strategies often lack mechanistic selectivity. Glycyrrhizic acid (GL), a major triterpenoid saponin from Glycyrrhiza species, exhibits broad anti-inflammatory effects, but its mechanism has been viewed as non-specific. In this review, we propose an integrated framework positioning high-mobility group box 1 (HMGB1) as one major molecular hub for GL’s action. Mechanistically, our molecular docking analysis suggests that GL may interact with the Box B domain of HMGB1 andmay potentially interfere with its engagement with TLR4 and RAGE, thereby orchestrating a cascade inhibition of downstream NF-κB, MAPK, and NLRP3 inflammasome pathways. Beyond this core signaling axis, we systematically analyze how GL context-dependently modulates macrophage polarization, monocyte-derived macrophage differentiation, and Th17/Treg balance. We further synthesize its effects across liver, autoimmune, metabolic, oncologic, neurological, and renal diseases, revealing shared mechanisms and disease-specific adaptations. Finally, we critically evaluate translational bottlenecks—including isomer-specific bioavailability, the pseudoaldosteronism risk, and formulation challenges—and propose strategies to overcome them. By shifting from a descriptive summary to a mechanism-centered, integrative analysis, this review provides a conceptual framework for developing GL as a multitarget anti-inflammatory agent, while acknowledging its limitations including low oral bioavailability, microbiota-dependent metabolism, pseudoaldosteronism risk, and limited clinical evidence.